Vol. 281, Issue 3, 1317-1329, 1997

Alprazolam in Young and Elderly Men: Sensitivity and Tolerance to Psychomotor, Sedative and Memory Effects¹

Richard J. Bertz² , Patricia D. Kroboth, Frank J. Kroboth, Ian J. Reynolds, Firoozeh Salek, C. Eugene Wright and Randall B. Smith

Clinical Pharmaceutical Scientist Program, Departments of Pharmacy and Therapeutics (R.J.B., F.S.S.) and Pharmaceutical Sciences (P.D.K.), School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania; Departments of Medicine (F.J.K.) and Pharmacology (I.J.R.), School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania; Clinical Pharmacokinetics, The Upjohn Company, Kalamazoo, Michigan (C.E.W.); and Novum Inc., Pharmaceutical Research Services, Pittsburgh, Pennsylvania (R.B.S.)

This study was designed to determine whether age influences sensitivity to alprazolam and/or rate of acute tolerance development to the effects of alprazolam. Three treatments were each separated by 4 weeks. Twenty-five young (ages 22- 35) and 13 elderly (ages 65-75) men received 2 mg of alprazolam/2 min i.v. Blood samples were obtained over 48 hr, and sedative, psychomotor and memory effects were assessed serially for 12 hr. Clearance was lower (P = .05) and elimination t_[1/2] was longer (P = .005) in the elderly, but area under the concentration curve to 12 hr and maximum concentration did not differ by age group. Maximum impairment was greater in the elderly for all assessments. Mean EC₅₀ values differed between the elderly (25.3 and 25.0 ng/ml) and the young (39.8 and 36.5 ng/ml) on card sorting and digit symbol substitution, respectively (P < .001). Bolus treatment data were used to individualize doses for the crossover of placebo and alprazolam; infusions were designed to maintain a plateau alprazolam concentration between 1 and 9 hr. Alprazolam concentrations through 12 hr did not differ between the young and elderly. Median t_[1/2] for offset of effect for digit symbol substitution was 2.8 hr in the young and 4.9 hr in the elderly (P = .05). Therefore, aging decreases alprazolam clearance and increases sensitivity to effects of alprazolam through a mechanism other than pharmacokinetics; aging also decreases the rate of offset of effect of alprazolam. In addition, the data provide insight into the intensity of initial effect as a determinant of rate of tolerance development.